All references, including any patents or patent applications, cited in this specification are hereby incorporated by reference. No admission is made that any reference constitutes prior art. The discussion of the references states what their authors assert, and the applicants reserve the right to challenge the accuracy and pertinency of the cited documents. It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country.
G protein-coupled receptors are prevalent throughout the human body, comprising approximately 60% of known cellular receptor types, and mediate signal transduction across the cell membrane for a very wide range of endogenous ligands. They participate in a diverse array of physiological and pathophysiological processes, including, but not limited to those associated with cardiovascular, central and peripheral nervous system, reproductive, metabolic, digestive, immunological, inflammatory, and growth disorders, as well as other cell-regulatory and proliferative disorders. Agents which selectively modulate functions of G protein-coupled receptors have important therapeutic applications. These receptors are becoming increasingly recognised as important drug targets, due to their crucial roles in signal transduction (G protein-coupled Receptors, IBC Biomedical Library Series, 1996).
One of the most intensively studied G protein-coupled receptors is the receptor for C5a. C5a is one of the most potent chemotactic agents known, and recruits neutrophils and macrophages to sites of injury, alters their morphology; induces degranulation; increases calcium mobilisation, vascular permeability (oedema) and neutrophil adhesiveness; contracts smooth muscle; stimulates release of inflammatory mediators, including histamine, TNF-α, IL-1, IL-6, IL-8, prostaglandins, and leukotrienes, and of lysosomal enzymes; promotes formation of oxygen radicals; and enhances antibody production (Gerard and Gerard, 1994).
Agents which limit the pro-inflammatory actions of C5a have potential for inhibiting chronic inflammation, and its accompanying pain and tissue damage. For these reasons, molecules which prevent C5a from binding to its receptors are useful for treating chronic inflammatory disorders driven by complement activation. Because such compounds act upstream from the various inflammatory mediators referred to above, and inhibit the formation of many of these compounds, they may have a more powerful effect in alleviating or preventing inflammatory symptoms.
In our previous application No. PCT/AU98/00490, we described the three-dimensional structure of some analogues of the C-terminus of human C5a, and used this information to design novel compounds which bind to the human C5a receptor (C5aR), behaving as either agonists or antagonists of C5a. It had previously been thought that a putative antagonist might require both a C-terminal arginine and a C-terminal carboxylate for receptor binding and antagonist activity (Konteatis et al, 1994). We showed that in fact a terminal carboxylate group is not generally required either for high affinity binding to C5aR or for antagonist activity. Instead we found that a hitherto unrecognised structural feature, a turn conformation, was the key recognition feature for high affinity binding to the human C5a receptor on neutrophils. As described in our international patent application No. PCT/AU02/01427, filed on 17th Oct. 2002, we used further refinements of these findings to design more tightly constrained structural templates which enable hydrophobic groups to be assembled into a hydrophobic array for interaction with a C5a receptor. We have subsequently found that a preferred compound of this class is able to inhibit cardiac and pulmonary fibrosis, and this is described in our international patent application No. PCT/AU03/00415, filed on 7th Apr. 2003. The entire disclosures of these specifications are incorporated herein by this reference.
Inflammatory bowel disease (IBD) is a group of serious, chronic relapsing inflammatory diseases affecting both the small and large intestine, which remains relatively resistant to current treatments. IBD is characterized by spontaneously occurring, chronic relapsing inflammation of unknown origin, in which current treatment options are inadequate (reviewed by van Deventer, 2002). Despite extensive research into the disease in both humans and experimental animals, the precise mechanisms of pathology remain to be elucidated. A host of immune and inflammatory mediators are thought to be involved, including biogenic amines, kinins, arachidonic acid metabolites, free radicals, nitric oxide, various proinflammatory cytokines, and complement proteins (Nielsen et al, 1996). Recent advances in drug development for IBD have involved the use of monoclonal antibodies to inhibit pro-inflammatory cytokines, such as interleukins, interferons and tumour necrosis factor α (TNF-α). In particular, the anti-TNF-α antibodies CDP571 and infliximab have been used clinically to treat Crohn's disease with some success. However, these new protein therapies suffer from major drawbacks, such as the costs of production, instability, poor bioavailability, limited routes of administration, and immunogenicity.
Several major forms of IBD are known, and Crohn's disease (regional bowel disease) and ulcerative colitis are the most common of these disorders. Because of the nature of their pathology, there are a number of autoimmune and immune-mediated diseases of the small and large bowel which are likely to benefit from treatment with these C5a antagonists. These include lymphocytic-plasmocytic enteritis, coeliac disease, collagenous colitis, lymphocytic colitis and eosinophilic enterocolitis. Other less common forms of IBD include indeterminate colitis, infectious colitis (viral, bacterial or protozoan, e.g. amoebic colitis), pseudomembranous colitis (necrotizing colitis), and ischemic inflammatory bowel disease. These conditions have been diagnosed in humans and in a number of animal species.
In 1999, approximately 1.7 million people in the United States alone were diagnosed with this debilitating disease. Satisfactory treatment of IBD is an unmet medical need, as existing therapeutic agents have not been successful in curtailing the disease and avoiding the need for surgery. Up to 40% of all ulcerative colitis patients undergo surgery, which typically includes either the removal of part of the large intestine or a full colostomy. While surgery is not curative for Crohn's disease, 75% of all patients will undergo at least one surgery in their lifetime, and up to 90% of these patients require additional surgeries. A therapeutic agent which can successfully treat inflammatory bowel disease can enormously improve a patient's quality of life, while potentially saving the healthcare system millions of dollars in costs associated with invasive surgical procedures.
In these conditions, chronic inflammation, caused by a number of inflammatory mediators, has been implicated in pathogenesis. The complement system has been acknowledged as one of these inflammatory mediators, since increased levels of complement products are found in the colons of patients with IBD (Neilsen et al. 1996). Ulcerative colitis, also known as idiopathic colitis, is characterized by inflammation of the colon and rectum, which become inflamed and ulcerated; its cause is unclear, although antibodies to colonic epithelium and E. coli strain 0119 B14 are often present. Its severity varies, and the patients suffer frequent relapses. Crohn's disease, also called regional enteritis or regional ileitis, is characterized by inflammation, thickening and ulceration of the bowel wall, usually in the terminal part of the ileum, with oedematous mucosa or thickened soft tissue, mesenteric infiltration, thickened bowel wall, and often inflammatory masses, abscesses, or distended fluid-filled loops. Complications include fistulae, intramural sinus tracts, abscesses, perforations, toxic megacolon, obstruction of the bowel, or hydronephrosis, and there is an increased risk of adenocarcinoma in the ileum or colon.
In both these conditions extensive bed rest is often required, and in severe case the affected part of the bowel may be surgically removed, necessitating the use of an ostomy bag. The only therapeutic agents which are available are corticosteroids such as prednisolone, monoclonal antibodies directed against tumour necrosis factor, such as Remicade (infliximab), immunosuppressive agents such as methotrexate, azathioprine, cyclosporine, tacrolimus and mycophenolate mofetil, or other anti-inflammatory agents such as sulphasalazine. These agents, especially the steroids, may be of limited effectiveness, and may have serious side effects. A variety of other agents, including corticosteroid derivatives such as budesonide, antagonists and agonists of cytokines such as interleukin-10 and interleukin-11, and a nicotinic receptor agonist, are in various stages of clinical trial. To our knowledge none of these approved or experimental agents, and in particular no small molecule agent, targets the C5a receptor.
Therefore there is a great need in the art for effective, non-toxic agents which do not require administration by injection, and which can be produced at reasonable cost.